Over the past few decades, catalysts based on precious metals have dominated organic catalytic chemistry and enabled the expeditious synthesis and discovery of numerous valuable organic compounds including natural products, pharmaceuticals, and advanced materials. However, precious metals are not earth-abundant, are expensive, and are susceptible to supply fluctuations. For these reasons, there is a critical need to develop efficient, sustainable catalysts based on earth-abundant elements that can outperform/supplement traditional precious metal catalysts in high-value transformations and which may do so via unconventional reaction pathways (Bullock, R. M., Catalysis Without Precious Metals (Wiley, 2010); Bullock, R. M., Science 342, 1054-1055 (2013); National Research Council, The Role of the Chemical Sciences in Finding Alternatives to Critical Resources: A Workshop Summary (The National Academies Press, 2012); Eijsbouts, S. et al., Appl. Catal. A 458, 169-182 (2013); and Wender, P. et al., Nature 469, 23-25 (2011)).
The dearomatization of aromatic compounds is one example of an especially challenging processes, and among these, selective dearomatization of six-membered nitrogenous heterocycles is an important transformation that provides straightforward access to diverse structural motifs present in many naturally-occurring and pharmacologically-active molecules (FIG. 1a) (Pape, A. R. et al., Chem. Rev. 100, 2917-2940 (2000); Roche, S. P. et al., Angew. Chem. Int. Ed. 50, 4068-4093 (2011)). For example, vinblastine, vincristine, and codeine are on the World Health Organization's List of Essential Medicines and like many other heavily prescribed drugs (e.g., Plavix, Abilify) incorporate dearomatized azine rings. Various dihydropyridines have a widespread natural occurrence and are used to treat a broad spectrum of medical conditions, such as cardiovascular and Alzheimer's diseases, dementia, diabetic neuropathy, and multidrug-resistant cancers (Stout, D. M. et al., Chem. Rev. 82, 223-243 (1982); Edraki, N. et al., Drug Discovery Today 14, 1058-1066 (2009)). Note also that 1,2-dihydropyridines are particularly useful synthetic intermediates in the preparation of complex nitrogen-containing natural products and pharmaceutical targets, as exemplified by a practical asymmetric synthesis of the influenza drug (−)-oseltamivir (FIG. 1b) (Lavilla, R., J. Chem. Soc. Perkin Trans. 1 1141-1156 (2002); Wender, P. A. et al., J. Am. Chem. Soc. 102, 6157-6159 (1980); Mizoguchi, H. et al., Nature Chem. 6, 57-64 (2014); Duttwyler, S. et al., Angew. Chem. Int. Ed. 53, 3877-3880 (2014); and Satoh, N. et al., Angew. Chem. Int. Ed. 46, 5734-5736 (2007)). Because of their importance, many synthetic strategies have been developed for the preparation of 1,2-dihydropyridines, however, most employ stoichiometric activating reagents, are not highly selective, often require harsh reaction conditions, and suffer from competing over-reductions (Bull, J. A. et al., Chem. Rev. 112, 2642-2713 (2012)).
Only recently have catalysts based on magnesium or rhodium demonstrated activity for pyridine 1,2-hydroboration to afford the corresponding N-boryl-1,2-dihydropyridine derivatives (FIG. 1c) (Arrowsmith, M. et al., Organometallics 30, 5556-5559 (2011); Oshima, K. et al., J. Am. Chem. Soc. 134, 3699-3702 (2012); and Osakada, K. et al., Angew. Chem. Int. Ed. 50, 3845-3846 (2011)). Despite such progress, these approaches have significant limitations, including functional group compatibility, regioselectivity, and the high cost of rhodium (Hao, L. et al., Angew. Chem. Int. Ed. 37, 3126-3129 (1998); Gutsulyak, D. V. et al., Angew. Chem. Int. Ed. 50, 1384-1387 (2011); Lee, S.-H. et al., Organometallics 32, 4457-4464 (2013)). Therefore, selective catalytic 1,2-dearomatization of diverse azines using earth-abundant catalysts under mild reaction conditions and with broad functional group compatibility remains a challenge.
Unlike platinum group metals, lanthanide catalysts are attractive due to the earth-abundance of these sustainable metals (comparable to that of Ni, Co, Cu), low toxicity, low cost (La is >2000× cheaper than Rh in per-mole prices), relatively stable supply, scarcely explored heterocycle reactivity, and mild conditions employed in the present catalytic reactions (Weiss, C. J. et al., Dalton Trans. 39, 6576-6588 (2010)). The efficient organolanthanide-catalyzed anti-Markovnikov hydroboration (and hydrosilylation) of olefins has previously been reported (FIG. 1d) (Harrison, K. N. et al., J. Am. Chem. Soc. 114, 9220-9221 (1992); Hong, S. et al., Acc. Chem. Res. 37, 673-686 (2004); and Fu, P.-F. et al., J. Am. Chem. Soc. 117, 7157-7168 (1995)). Mechanistically, the reaction proceeds via addition of a labile Cp*2Ln-H bond across the C═C functionality, followed by rapid Ln-C . . . H—B σ-bond transposition. The challenge of hydroborating multiple carbon-heteroatom bonds should be addressed, specifically the notably unreactive C═N functionalities of azines (Obora, Y. et al., J. Am. Chem. Soc. 119, 3745-3755 (1997)).
To cure the deficiencies of the prior art, a general catalytic approach to the efficient, regioselective 1,2-dearomatization of diverse pyridines and other azines using pinacolborane (HBpin), along with a detailed kinetic and computational mechanistic analysis is provided herein. This reaction is catalyzed by 1% [Cp*2LaH]2 (1) under mild, atom-efficient reaction conditions (FIG. 1e) (Jeske, G. et al., J. Am. Chem. Soc. 107, 8091-8103 (1985)). Regarding lanthanide abundance, recent reports forecast near-term stabilization of both price and supply. Indeed, initiatives by many governments, WTO rulings against monopolistic practices and trade violations, as well as reopening of closed and the development of new mining facilities have triggered a rapid worldwide decline in lanthanide prices to the pre-2011-crisis levels, thus providing assurance of a continuous, sustainable future supply of low-cost lanthanide metals (Humphries, M., Rare Earth Elements: The Global Supply Chain (Congressional Research Service, 2013)).